All components are phylogenetically older means of protecting the body (compared to the immune system), which, without the participation of lymphocytes and antibodies, can act on a wide range of infectious agents.
The resistance system is activated by inducers of inflammation and suppressed by its inhibitors. Compared to immunity, the non-specific resistance system varies considerably due to temporal and individual differences. The synthesis of all components is genetically determined, they are present in the body at the time of birth. Thanks to the balance immune system and the system of nonspecific resistance, the preservation of the individual integrity of a highly developed organism is achieved. On the other hand, partial defects and violations of regulatory mechanisms lead to numerous diseases.
Phagocytic system. Phagocytosis is the active uptake of solid material by cells. In unicellular organisms, this process serves mainly for nutrition. Many multicellular organisms, including humans, phagocytosis serves as a fundamental mechanism of anti-infective defense. Phagocytes are cells with a particularly pronounced ability to phagocytosis. Morphologically and functionally, monocytic (macrophages) and granulocytic (granulocytes and microphages) components of the phagocytic system are distinguished. All phagocytes have the following functions:
- migration and chemotaxis;
- adhesion and phagocytosis;
- cytotoxicity;
- secretion of hydrolases and other biologically active substances.
Mononuclear phagocytes are capable of limited proliferation outside the bone marrow, of the synthesis and secretion of numerous proteins, and are involved in the processes of tissue differentiation and maturation. In addition, macrophages are antigen-presenting cells, i.e., they process and present an antigen for recognition by cells of the immune system and thereby trigger the mechanism immune response.
Granulocyte system of phagocytosis. Granulocytes are generated during granulopoiesis in bone marrow. They are characteristic a large number of granulocytes in the cytoplasm, according to the ability to stain which distinguish between basophilic, eosinophilic and neutrophilic granulocytes. From the standpoint of assessing the human resistance system, polymorphonuclear neutrophils (PMN) are of great importance, which is determined both by their number and function. The maturation time of PMN in the bone marrow is from 8 to 14 days. Then they enter the bloodstream as mature, incapable of dividing cells with a diameter of 10-12 microns with a complex segmented nucleus. Many cells contain appreciable amounts of weakly azurophilic cytoplasmic granules as well as a folded membrane. After a few hours, polymorphonuclear neutrophils leave the bloodstream into the interstitial space and die after 1-2 days. different types granulocytes are involved in all forms of inflammation and play a leading role in this. A close relationship is revealed between macrophages and polymorphonuclear neutrophils, as well as eosinophilic and basophilic granulocytes. Polymorphonuclear neutrophils are the main component of human blood leukocytes. Every day, a lot of polymorphonuclear neutrophils come out of the bone marrow into the blood, and in acute infections this number can increase 10-20 times, while immature forms also appear in the blood (shift of the blood formula to the left). The size of myelopoiesis is determined and regulated by specific granulocyte growth factors produced by peripheral granulocytes and macrophages. The exit from the bone marrow and the accumulation of cells in the focus of inflammation are regulated by chemotaxis factors. PMN play a decisive role in anti-infective protection, which is carried out continuously in the body, so permanent agranulocytosis is not compatible with the concept of a living functioning organism. The activity of PMN is closely related to the granules, the content of which is represented by enzymes and other biologically active substances. At the promyelocyte stage, primary azurophilic granules appear in the cytoplasm of the cell; the so-called secondary (specific) granules are also detected in the myelocyte. These forms can be distinguished by electron microscopy and separated by fractionation of subcellular structures. Preparative ultracentrifugation also revealed the fraction of small granules corresponding to lysosomes of polymorphonuclear neutrophils. Regardless of the type, granules are cellular structures containing hydrolytic enzymes or proteins. They are surrounded by a lipoprotein envelope, which, when activated, can fuse with similar subcellular structures and cytoplasmic membrane.
The functional activity of polymorphonuclear neutrophils is regulated by a large number of membrane receptors, soluble and corpuscular activators. There are resting and activated polymorphonuclear neutrophils. The former have a rounded shape, circulate in the bloodstream and other body fluids and are characterized by the oxidative nature of metabolism. Adhesion to other cells, chemotactic factors and phagocytosis lead to the activation of polymorphonuclear neutrophils, which is determined by increased uptake of oxygen and glucose, as well as the release of carbon dioxide by cells. With phagocytosis or massive action of chemotactic factors, the need for cells in energy increases, which is achieved due to the monophosphate shunt. Under conditions of hypoxia, a short time with the help of glycolysis to obtain a sufficient supply of ATP. Subsequent reactions of activated polymorphonuclear neutrophils depend on the type of stimulation. Synthesis products are limited to metabolites arachidonic acid and other lipid factors.
Mononuclear phagocytic system. The dominant cells of the mononuclear phagocytic system are macrophages. The forms of manifestation of their activity are extremely heterogeneous. The general origin of cells depends on bone marrow monocytopoiesis, from where monocytes enter the blood, where they circulate for up to three days, and then migrate to adjacent tissues. Here, the final maturation of monocytes occurs either as mobile histiocytes (tissue macrophages), or into highly differentiated tissue-specific macrophages (alveolar macrophages of the lungs, Kupffer cells of the liver). The morphological heterogeneity of cells corresponds to the functional diversity of the mononuclear system. The histiocyte has a pronounced ability to phagocytosis, secretion and synthesis. On the other hand, dendritic cells from lymph nodes and spleen, as well as skin Langerhans cells are more specialized in the direction of antigen processing and presentation. Cells of the mononuclear phagocytic system can live from several weeks to several months, their diameter is 15-25 microns, the nucleus is oval or kidney-shaped. In promonocytes and monocytes, azurophilic granules are detected, and in mature macrophages, similar to cells of the granulocytic series. They contain a number of hydrolytic enzymes, other active substances and only traces of myeloperoxidase and lactoferrin. Bone marrow monocytopoiesis can be increased only 2-4 times. Cells of the mononuclear phagocytic system outside the bone marrow proliferate extremely limitedly. The substitution of cells of the mononuclear phagocytic system in tissues is carried out by blood monocytes. It is necessary to distinguish between resting and activated macrophages, and activation can affect a wide variety of cell functions. Macrophages have all the functions of cells of the mononuclear phagocytic system, in addition, they synthesize and secrete a large number of proteins into the extracellular environment. Hydrolases are synthesized by macrophages in large quantities and either accumulate in lysosomes or are immediately secreted. Lysozyme is continuously produced in cells and also secreted; under the action of activators, its level in the blood rises, which makes it possible to judge the state of activity of the mononuclear phagocytic system. Metabolism in macrophages can proceed both along the oxidative and glycolytic pathways. Upon activation, an “oxygen explosion” is also observed, which is realized through a hexose monophosphate shunt and manifests itself in the formation of reactive oxygen species.
Specific functions of phagocytes. Phagocytosis is a characteristic function of phagocytes, it can occur in various ways and be combined with other manifestations of functional activity:
- recognition of chemotactic signals;
- chemotaxis;
- fixation on a solid substrate (adhesion);
- endocytosis;
- reaction to non-phagocytic (due to size) aggregates;
- secretion of hydrolases and other substances;
- intracellular disintegration of particles;
- removal of decay products from the cell.
Cytotoxic and inflammatory mechanisms. Activated phagocytes are highly efficient cytotoxic cells. In this case, the following mechanisms should be subdivided:
1) intracellular cytolysis and bactericidal activity after phagocytosis;
2) extracellular cytotoxicity:
- contact cytotoxicity (phagocyte and target cell are associated with each other for at least a short time);
- distant cytotoxicity (phagocyte and target cell are adjacent to each other, but do not directly contact).
Intracellular and contact types Cytotoxicity may be immunological (mediated by antibodies) or non-specific. Distant cytotoxicity is always non-specific, i.e., it is induced by toxic enzymes and reactive oxygen species from activated macrophages. This category includes cytotoxic effects on tumor cells mediated by tumor necrosis factor and interferon alpha.
In the framework of anti-infective protection, bactericidal activity of phagocytes, which manifests itself intracellularly after phagocytosis of microorganisms, is of great importance. Microscopy of phagocytosis of neutrophilic granulocytes shows more or less pronounced degranulation of cells. We are talking about the fusion of specific and azurophilic granules with the phagosome and the cytoplasmic membrane. Lysosomal enzymes and biologically active substances are secreted both into the phagosome and into the environment. In this case, hydrolases are activated, which act outside the cell as factors that promote inflammation and mediate distant cytotoxicity. Their maximum concentration is noted in the phagolysosome, resulting in rapid degradation of proteins, lipids and polysaccharides. It should be noted that microorganisms have a membrane that is relatively resistant to the action of lysosomal enzymes, but it must be destroyed in the phagolysosome. There are O2-dependent and O2-independent mechanisms of cytotoxicity and bactericidal activity of phagocytes.
Oxygen non-dependent cytotoxicity. In the area of inflammation with impaired microcirculation, hypoxia and anoxia, phagocytes are characterized by limited viability and activity due to glycolytic metabolism. The bactericidal activity of phagolysosomes is determined by acidic pH values, the content of a number of toxic cationic proteins, acid hydrolases and lysozyme. Activated PMNs and macrophages are also capable of independent contact cytotoxicity. It may be due to ADCC or other non-specific mechanisms directed, for example, to tumor cells. The biochemical basis of this phenomenon is not yet known. Dependent and independent cytotoxicity are predominantly cumulative, but a number of lysosomal hydrolases are inactivated free radicals. The mutual influence of various lysosomal hydrolases, proteinases, lipases, on the one hand, and cationic proteins together with enzyme inhibitors, on the other, cannot be fully covered.
The mechanisms of bactericidal activity of granulocytes and macrophages are similar. Depending on the localization, macrophages can act both anti-inflammatory and cause inflammation. These effects are due to the processes of secretion and synthesis.
Functions of secretion and synthesis of phagocytes. Along with chemotaxis and phagocytosis, secretion is one of the fundamental functions of phagocytes. All 3 functions are closely related to each other, and synthesis and secretion are necessary for the cooperation of leukocytes with endothelial cells, platelet activation, regulation of the endocrine glands and hematopoiesis. In addition, protein synthesis in macrophages and their secretion are important for the blood coagulation system, the complement system, and the kinin system. Several processes should be distinguished:
1) emptying of granules or lysosomes of macrophages and granulocytes;
2) synthesis and secretion of active lipids;
3) synthesis and secretion of numerous proteins in macrophages.
Macrophages synthesize a number of complement system factors and themselves carry receptors for some activation products of this system. Of particular importance for the immune system is the synthesis of interleukin-1 by cells of the macrophage system, which, on the one hand, induces the proliferation of lymphocytes, and on the other hand, activates protein synthesis. acute phase in the liver and contributes to an increase in body temperature (endogenous pyrogen).
Through the synthesis of interferon, macrophages regulate the body's resistance to viral infection. A significant role in the regulation of resistance by macrophages is played by the synthesis by these cells of colony-stimulating factors G-CSF, GM-CSF) myelo- and monocytopoiesis of the bone marrow. A wide range of functions performed by macrophages makes it possible to evaluate their role in the pathogenesis of diseases that occur both with and without inflammatory manifestations. Comparison of data on the properties of macrophages with information on other cells of the resistance system and the immune system allows us to conclude that our knowledge is rather limited. The use of molecular biology and genetic engineering methods makes it possible to obtain macrophage synthesis products in a purified form and in significant quantities. To the most interesting known factors macrophages include tumor necrosis factor and interferon. Due to its properties, the macrophage system is central to the defense against bacterial, viral and neoplastic diseases.
Null lymphocytes do not have surface markers on the plasmalemma characteristic of B and T lymphocytes. They are regarded as a reserve population of undifferentiated lymphocytes.
Currently, the assessment of the immune status of the body in the clinic is carried out using immunological and immunomorphological methods for detecting various kinds lymphocytes.
The lifespan of lymphocytes varies from a few weeks to several years. T-lymphocytes are "long-lived" (months and years) cells, and B-lymphocytes are "short-lived" (weeks and months). T-lymphocytes are characterized by the phenomenon of recirculation, i.e. exit from the blood to the tissues and return through the lymphatic pathways back to the blood. Thus, they carry out immunological surveillance of the state of all organs, quickly responding to the introduction of foreign agents. Among the cells that have the morphology of small lymphocytes, circulating blood stem cells (HSCs), which enter the blood from the bone marrow, should be mentioned. These cells were first described by A.A. Maksimov and designated by him as "mobile mesenchymal reserve". From the HSC entering the hematopoietic organs, differentiate various cells blood, and from HSC entering the connective tissue - mast cells, fibroblasts, etc.
Monocytes. System of mononuclear phagocytes (MPS).
In a drop of fresh blood, these cells are only slightly larger than other leukocytes (9-12 microns), in a blood smear they are strongly spread on the glass and their size reaches 18-20 microns. In human blood, the number of monocytes ranges from 6-8% of the total number of leukocytes.
The nuclei of monocytes are of diverse and variable configuration: there are bean-shaped, horseshoe-shaped, rarely lobulated nuclei with numerous protrusions and depressions. Heterochromatin is scattered in small grains throughout the nucleus, but usually in large quantities it is located under the nuclear membrane. The monocyte nucleus contains one or more small nucleoli (Fig. 8).
Fig.8. Monocyte.
The cytoplasm of monocytes is less basophilic than that of lymphocytes. When stained according to the Romanovsky-Giemsa method, it has a pale blue color, but along the periphery it is painted somewhat darker than near the nucleus; it contains a variable number of very small azurophilic grains (lysosomes). The presence of finger-like outgrowths of the cytoplasm and the formation of phagocytic vacuoles are characteristic. Numerous pinocytic vesicles are located in the cytoplasm. There are short tubules of the granular endoplasmic reticulum, as well as small mitochondria. Monocytes belong to the macrophage system of the body, or to the so-called mononuclear phagocytic system (MPS). The cells of this system are characterized by their origin from bone marrow promonocytes, the ability to attach to the glass surface, the activity of pinocytosis and immune phagocytosis, and the presence of receptors for immunoglobulins and complement on the membrane. Circulating blood monocytes are a mobile pool of relatively immature cells on their way from the bone marrow to the tissues. The residence time of monocytes in the blood varies from 36 to 104 hours. Monocytes that migrate into tissues turn into macrophages, while they have a large number of lysosomes, phagosomes, and phagolysosomes.
7.0-106 monocytes leave the blood in tissues in 1 hour. In tissues, monocytes differentiate into organ- and tissue-specific macrophages. The extravascular pool of monocytes is 25 times greater than the circulating pool.
The system of mononuclear phagocytes is the central, unifying Various types cells involved in defensive reactions organism. Macrophages play an important role in the processes of phagocytosis. They remove dead cells, remnants of destroyed cells, denatured protein, bacteria and antigen-antibody complexes from the body. Macrophages are involved in the regulation of hematopoiesis, immune response, hemostasis, lipid and iron metabolism. The content of monocytes in the blood is normally reflected in table.2.
Table 3
Monocytosis- an increase in the number of monocytes in the blood (> 0.8109 / l) - accompanies a number of diseases (Table 1.28). In tuberculosis, the appearance of monocytosis is considered evidence of the active spread of the tuberculosis process. Wherein important indicator is the ratio of the absolute number of monocytes to lymphocytes, which is normally 0.3-1.0. This ratio is more than 1.0 in the active phase of the disease and decreases during recovery, which makes it possible to assess the course of tuberculosis.
With septic endocarditis, sluggish sepsis significant monocytosis is possible, which often occurs in the absence of leukocytosis. Relative or absolute monocytosis is noted in 50% of patients with systemic vasculitis.
Short-term monocytosis may develop in patients with acute infections during the recovery period. Monocytopenia - a decrease in the number of monocytes (< 0,09109/л). При гипоплазии кроветворения количество моноцитов в крови снижено.
2.3 Postcellular structures
2.3.1 Red blood cells
Erythrocytes, or red blood cells, of humans and mammals are non-nucleated cells that have lost the nucleus and most of the organelles in the process of phylo- and ontogenesis. Erythrocytes are highly differentiated postcellular structures incapable of division.
The functions of erythrocytes are carried out in the vascular bed, which they normally never leave:
1) respiratory - transportation of oxygen and carbon dioxide. This function is ensured by the fact that erythrocytes are filled with iron-containing oxygen - a binding pigment - hemoglobin (makes up 33% of their mass), which determines their color (yellowish for individual elements and red for their mass)
2) Regulatory and protective functions are provided due to the ability of erythrocytes to carry on their surface a number of biologically active substances, including immunoglobulins, complement components, immune complexes.
3). In addition, erythrocytes are involved in the transport of amino acids, antibodies, toxins and a number of medicinal substances, adsorbing them on the surface of the plasma membrane.
MONONUCLEAR PHAGOCYTE SYSTEM(syn.: macrophage system, monocyte-macrophage system) - a system that unites cells, to-rye have the ability to endocytosis, have a common origin, morphological, cytochemical and functional similarity. The concept of S. m. f. first proposed in 1969 at a conference in Leiden instead of the outdated concept of the reticuloendothelial system (see Reticuloendothelial system). At subsequent conferences in Leiden (1973, 1978), ideas about S. m. f. continued to be improved, and this concept is now accepted by most researchers.
The basis of the concept of S. m. f. modern ideas about the common origin and kinetics of these cells, their morphological, cytochemical, and functional similarities have been established. Mononuclear phagocytes are present in all tissues, but in normal conditions proliferation of their precursors occurs only in the bone marrow (see). The earliest recognized precursors of the series of differentiation of these cells are monoblasts - direct "descendants" of switched stem cells. As a result of the division of monoblasts, promonocytes appear - direct precursors of monocytes (see Hematopoiesis). Monocytes enter the bloodstream and then migrate to various fabrics and body cavities where they become macrophages (see). Experimental studies have confirmed the origin of macrophages different localization from circulating monocytes. It has also been shown that the division of macrophages in tissues essential does not have for their renewal, whereas reticular cells, reticular dendritic cells, fibroblasts, endothelial and mesothelial cells do not have precursors in the bone marrow, but are renewed by local division in tissues. The scheme shows the origin of the cells that make up the system of mononuclear phagocytes, and their localization in organs and tissues, the types of macrophages in the norm and during inflammation, depending on its nature (Fig. 1).
The function of the system of mononuclear phagocytes is controlled by complex regulatory mechanisms that ensure the entry of macrophages into tissues under normal and pathological conditions. For description functional state macrophages, a variety of definitions are used (activated, immune, armed, induced, stimulated, exudative, etc.). Macrophage activation occurs during in vitro cultivation, phagocytosis of bacteria, contact with antigen, immune complexes, bacterial lipopolysaccharides, polynucleotides, and interaction with lymphokines (see Mediators of Cellular Immunity). In particular, in vitro participation in monocytopoiesis (and granulocytopoiesis) of glycoprotein regulators, or the so-called. colony-stimulating factors, to-rye affect the rate of differentiation of precursors of macrophages and belong to az-globulins with a molecular weight (mass) from 13,000 to 93,000. With various pathological processes when the need for monocytes increases, the production of the latter increases due to the entry into the cycle of non-proliferating promonocytes (normally, only about 40% of promonocytes actively proliferate in humans) and shortening the cell cycle, which normally averages approx. 30 hours. Under conditions of inflammation, macrophages of the lesion produce and release a factor into the circulatory bed, which enhances monocytopoiesis and, reaching the bone marrow, stimulates the production of monocytes. This factor is a protein with a molecular weight (mass) of approx. 20,000. After the damaging agent is eliminated, macrophages begin to produce another factor - an inhibitor of monocytopoiesis with a molecular weight (mass) of approx. 50,000.
Activated macrophages are characterized by increased size, enhanced phagocytic, digestive and bactericidal functions. They increase the activity of acid hydrolases, metabolic processes. Morphologically activated macrophages are characterized by an increase in the number and size of lysosomes, an expansion of the Golgi complex, and an increase in the folding of the plasma membrane. Activated macrophages with an increased number of receptors for IgG have been described in patients suffering from sarcoidosis (see), Crohn's disease (see Crohn's disease) and tuberculosis (see).
A stimulant that has a pronounced and targeted effect on macrophages is glucan (a complex polysaccharide from the membranes of the yeast cells of Saccharomyces cerevisiae). Administration of glucan to mice results in sharp increase phagocytic activity of macrophages, stimulation of humoral and cellular immunity (see). At the same time, the antitumor effect of macrophages is clearly manifested. In parallel, the accumulation of macrophages in the liver, spleen and lungs was noted. Researchers using glucan emphasize the absence of any side effects in experimental animals.
Drugs that block or eliminate macrophages primarily prevent their participation in various immune responses. Thus, particles of captured colloidal carbon lead to the loss of the ability of macrophages to process the antigen or prepare it for interaction with the corresponding lymphocytes during the development of the immune response. The immunosuppressive effect of carrageenans (high molecular weight polygalactoses) and quartz particles on macrophages is based on their selective toxic effect. The same agents are used to study the participation of macrophages in certain processes.
The ways of migration of monocytes into tissues are different and not fully understood. In the lungs, for example, monocytes differentiate directly into alveolar macrophages, bypassing the maturation phase in the interstitium. IN abdominal cavity part of macrophages comes from milk spots (see), where they differentiate from monocytes. The ability of macrophages to recirculate through blood vessels it is very limited, however it is proved that they can migrate to nearby limf, nodes where they die.
Morphophysiology
The characteristic qualities inherent in S.'s cells mf, in particular macrophages (see), are the ability to endocytosis, including phagocytosis (see) and pinocytosis (see), adhesion, migration. tissue macrophages and serous cavities have a more or less spherical shape, a folded plasma membrane (cytolemma) and are characterized primarily by the presence in the cytoplasm of numerous lysosomes (see) and phagolysosomes, or digestive vacuoles (Fig. 2). In a scanning electron microscope (see Electron microscopy), superficial folds and ridges of macrophages are clearly visible (Fig. 3). Possessing a pronounced ability to adhere, under cultivation conditions, macrophages strongly spread out on the surface of the substrate and acquire a flattened shape. When moving along the substrate, they form many polymorphic pseudopodia (see Cell), and the scans show a folded leading edge directed towards cell movement, and long processes that fix the cell to the substrate. In addition, macrophages different localization, even within the same organ, for example. limf, node, differ both morphologically and functionally. So, macrophages of the light (germinative) centers unlike the fixed and free macrophages of sinuses limf, nodes do not phagocytize antigens, but absorb other foreign particles and lymphocytes. They are usually isolated as macrophages with staining inclusions.
The intracellular metabolism of mononuclear phagocytes depends on the stage of differentiation, tissue localization, activation, and endocytosis. The main sources of energy for mononuclear phagocytes are glycolysis, hexosomonophosphate shunt, and aerobic metabolism. Research recent years showed that macrophages are active secretory cells, to-rye release enzymes, inhibitors, factors and complement components into their environment (see). The main secretory product of macrophages is lysozyme (see), which is produced and secreted at a constant rate. Unlike lysozyme, some neutral proteinases are secreted mainly by activated macrophages. Among them, elastase (see), collagenase (see) and plasminogen activators (see. Fibrinolysis) involved in the destruction and restructuring of tissues (eg, bone resorption, involution of the mammary glands and postpartum involution of the uterus) are best studied. Both fixed and free macrophages secrete nek-ry complement factors, such as C2, C3, C4, C5, factor B, and interferon (see).
Research methods
Traditional morfol. methods, especially at the light-optical and even at the electron-microscopic level, are often insufficient for the identification of mononuclear phagocytes. Even when studying isolated cells, it is sometimes difficult to distinguish a monocyte from a lymphocyte or monocyte precursors (monoblast and promonocyte), from granulocyte precursors (myeloblasts and promyelocytes). In addition, tissue macrophages are often confused with reticular cells, fibroblasts, endothelial and mesothelial cells, although the separation of these cells is of fundamental importance, since their origin and function are completely different.
Only the use of specific markers in combination with electron microscopy makes it possible to reliably identify and evaluate the involvement of mononuclear phagocytes in certain processes. One of the most reliable markers for the identification of human and animal mononuclear phagocytes is the esterase enzyme (EC 3.1.1.1.), which is determined histochemically when using a-naphthyl butyrate or a-naphthyl acetate as a substrate. At the same time, almost all monocytes and macrophages are stained, although the intensity of histochemical. reactions may vary depending on the type and functional state of the organism, as well as on the conditions of cell cultivation. In mononuclear phagocytes, the enzyme is diffusely localized, while in T-lymphocytes it is detected as one or two punctate granules.
Another reliable marker is lysozyme (EC 3. 2. 1. 17.) - an enzyme secreted by macrophages, which can be detected using an immunofluorescent method using antibodies to lysozyme (see Immunofluorescence).
To reveal various stages of a differentiation of mononuclear phagocytes allows peroxidase (see). Granules containing the enzyme stain positively only in monoblasts, promonocytes, monocytes and macrophages of the exudate; resident (i.e., permanently present in normal tissues) macrophages do not stain.
51-nucleotidase (EC 3.1.3.5), leucine aminopeptidase (EC 3.4.11.1.), phosphodiesterase I (EC 3.1.4.1.) located in the plasma membrane. The activity of these enzymes is determined either in cell homogenates or cytochemically. Detection of Dn-nucleotidase makes it possible to distinguish between normal (resident) and activated macrophages (the activity of this enzyme is high in the former and low in the latter). The activity of leucine-aminopeptidase and phosphodiesterase, on the contrary, increases with the activation of macrophages.
Complement components, in particular C3, can also be a marker, since this protein is synthesized only by monocytes and macrophages. It can be detected in the cytoplasm using immunocytochemical methods; complement components in different animal species differ in antigenic properties.
Existence immunol is rather characteristic of mononuclear phagocytes. receptors for the Fc fragment of JgG (see Immunoglobulins) and for the C3 component of the complement. Mononuclear phagocytes carry these receptors at all stages of development, but among immature cells the number of mononuclear phagocytes with receptors is lower than among mature ones (monocytes and macrophages). Mononuclear phagocytes have the ability to endocytosis. Therefore absorption of opsonized bacteria or the erythrocytes covered with IgG (immune phagocytosis) is the important criterion allowing to carry a cell to S. m. f. However, absorption of complement-coated erythrocytes does not occur unless mononuclear phagocytes have been previously activated. In addition to phagocytosis, all mononuclear phagocytes are characterized by intense pinocytosis. In macrophages the macropinocytosis prevails, to-ry is the cornerstone of capture of all solutions; Vesicles formed as a result of internalization of the membrane (invagination of a section of the membrane into the cell) transport substances outside the cell. Pinocytosis was also noted in other cells (eg, in fibroblasts), but to a lesser extent. Non-toxic vital dyes and colloidal charcoal are not very suitable for characterizing the endocytic activity of mononuclear phagocytes, since they are also taken up by other cell types.
Antisera can be used to detect antigens specific to mononuclear phagocytes, but obtaining antibodies specific to these cells is still very difficult because many of the antisera contain antibodies that cross-react with other cell types.
At the cellular level, the ability of cells to divide is judged by the inclusion of the labeled DNA precursor 3H-thymidine or by the content of DNA in the nuclei.
The role of the system of mononuclear phagocytes in physiological and pathological processes
Mononuclear phagocytes are polyfunctional cells, which, having a pronounced ability to endocytosis, perform a protective function in the body, take part in inflammation processes, immune reactions, have antitumor activity, participate in the regulation of hematopoiesis and metabolism.
Protective function
The protective function of mononuclear phagocytes is based on their ability to selectively absorb and destroy various foreign agents. The term "professional phagocytes" was assigned to them, since absorption (endocytosis) is their main function. Monocytes and macrophages are capable of directional movement determined by specific chemotactic factors. The regulation of these factors is complex; their inhibitors and inactivators have been identified in human blood serum. In vivo chemotaxis (see Taxis) is caused by complement components C3 and C4, kallikrein, fibrinolysis components, lymphocyte products - lymphokines. Macrophages are also attracted by substances released from bacteria. Thanks to chemotaxis, macrophages migrate to the foci of infection and inflammation. After phagocytosis of microorganisms, they are killed and digested. As the phagocytic vacuoles move into the cell, they release substances that are in lysosomes, capable of hydrolyzing proteins, lipids and carbohydrates that are part of microorganisms. Some of the released components of macrophages, such as peroxidase, lysozyme, etc., have antimicrobial activity. Lysozyme is an antibacterial agent outside of cells. The environment in phage-lysosomes becomes acidic, which contributes to the manifestation of optimal activity of lysosome enzymes. At the same time, a sharp increase in metabolism occurs in phagocytic cells. Digestion is completed within one to two hours. Activated macrophages, like neutrophils, release hydrogen peroxide and superoxide anions into the environment and, with their help, can lyse various target cells. Macrophages also capture viruses, and some of them enter the cell by pinocytosis. The main function of the Kupffer cells of the liver is the clearance (purification) of the blood from bacteria and viruses. Old or damaged red blood cells are phagocytosed by macrophages in the bone marrow, spleen, and liver, and then subjected to intracellular digestion (erythrophagocytosis).
Participation in inflammation
Damaging agents (agents-irritants) of various nature cause in general the same type of reaction of the body - inflammation (see). A single short-term irritation induces the migration of neutrophils and their accumulation in the area of damage. After 6 hours. the influx of neutrophils gradually weakens, after which the migration of macrophages begins, the edge continues for about 3 days, and then decreases. Macrophages in the focus of acute inflammation are formed only from circulating monocytes. With subacute and chronic inflammation, macrophages often become dominant cells, and if the acute inflammatory process goes into hron. form, then local proliferation and selection of long-lived macrophages are observed, aimed at maintaining the number of macrophages in the focus of inflammation.
The turnover of macrophages in the lesion depends on the nature of the irritating agent. If the provocative agent is eliminated, they disappear (they die or migrate to the lymph nodes). While maintaining the action of the causative agent of inflammation, macrophage infiltrate remains. If in the process of a response aimed at eliminating a toxic and persistent irritant (eg, silicon dioxide, bacteria), a large number of macrophages are lost, then a granuloma is formed (see) with a high level of cell turnover. If the irritant is resistant to the action of macrophages and at the same time non-toxic, a granuloma occurs with low level cell turnover; in such a granuloma, long-lived macrophages predominate. In many specific granulomas (eg, in tuberculosis, sarcoidosis, leprosy), mononuclear phagocytes transform into epithelioid cells (Fig. 4) with weak phagocytic activity, but strongly pronounced pinocytosis and the ability to secrete. In the centers hron. inflammation, mononuclear phagocytes, when fused, give rise to the so-called. macrophage polykaryons, or multinuclear giant cells of foreign bodies (Fig. 5) and Pirogov-Langhans type cells (see Giant cells). The latter usually retain a very weak phagocytic activity, for example, against tuberculosis bacteria. In chron. granulomas caused by quartz particles, there is a continuous death of macrophages as a result of the destruction of lysosomes and self-digestion of cells. At the same time, a fibrogenic factor is released from the cells, which stimulates the synthesis of collagen by fibroblasts. In addition, activated macrophages produce fibronectin-glycoprotein with a high molecular weight, which is, in particular, a chemo-attractant (attracting agent) for fibroblasts.
Participation in immune processes
Cells of S. m. f. take part in immune processes. The primary interaction of a macrophage with an antigen (see) is an indispensable condition for the development of a directed and maximum immune response (see Immunity). As a result of this interaction, the antigen is absorbed and processed inside the macrophage (processing), after which it is secreted in an immunogenic form, being fixed on its plasma membrane. Immune stimulation of lymphocytes occurs as a result of their direct contact with macrophages. In the future, the immune reaction proceeds with the participation of B-lymphocytes, T-lymphocytes and macrophages (see Immunocompetent cells).
Antitumor activity
Macrophages have antitumor activity and exhibit specific and nonspecific cytotoxic properties due to the presence of cytophilic antibodies or factors produced by sensitized T-lymphocytes. The destruction of target cells is usually assessed by the release of their associated radioactive chromium after incubation with cytotoxic macrophages - effectors. The cytotoxicity exhibited by macrophages is related to a number of immune responses, such as allograft rejection (see transplantation immunity) and antitumor immunity (see antitumor immunity).
Cytotoxic properties have two categories of effector macrophages: immune, or so-called. armed, macrophages, actively destroying specific target cells, and non-specific activated macrophages with less selective properties. The cytotoxicity of immune macrophages against tumor cells has been demonstrated in in vitro experiments, in which macrophages from mice immunized with syngeneic (genetically identical) tumor cells were used. At the same time, macrophages were not able to destroy tumor cells if they were obtained from mice immunized with allogeneic tumor cells (taken from another animal of the same species). The specific preparation (armament) of macrophages depends on the production of a specific factor by sensitized T-lymphocytes. The exact mechanism of cell destruction by armed macrophages is still unknown. For lysis tumor cells contact between them and macrophages is necessary. The process of destruction of tumor cells includes stopping their proliferation and lysis. Following a specific immune response between a macrophage and a tumor target cell, the macrophage may lose specificity. In this case, it turns into a nonspecific effector cell. Nonspecific cytotoxicity can be observed after incubation of macrophages with various substances: endotoxin, double-stranded RNA and Freund's adjuvant (see Adjuvants).
Participation in the regulation of hematopoiesis
Cells of S. m. f. take part in the regulation of myeloid and lymphoid hematopoiesis (see). In the red bone marrow, spleen, liver and yolk sac of the embryo, the so-called. central macrophage surrounded by one or two rows of erythroblasts. Thin cytoplasmic processes of the central macrophage penetrate between erythroblasts, and sometimes completely surround them. The central macrophage always becomes the center of erythropoiesis, together with erythroblasts adjacent to it, it received the name of an erythroblastic island, to-ry is considered as a functional and anatomical unit of erythropoiesis foci. The central macrophage engulfs the nuclei of erythroblasts, digests old erythrocytes, and transfers the accumulated iron to developing erythroblasts. Some decay products of absorbed nuclei can be reutilized for new DNA synthesis by hematopoietic cells. The central macrophage is highly resistant to ionizing radiation and hypoxia. Central macrophages are stromal elements and perform a regulatory function during the maturation of erythroid progenitor cells, for example. with phenylhydrazine anemia (see Anemia, experimental anemia). The appearance of new intravascular erythroblastic islands in the bone marrow, liver, and spleen is always associated with the presence of phagocytic macrophages that differentiate from monocytes circulating in the blood.
Kupffer cells of the liver are involved in the regulation of erythropoiesis through the production of erythropoietin (see).
Using agar cultures, it was found that monocytes and macrophages produce factors that stimulate the production of monocytes, neutrophils and eosinophils, as well as the proliferation of macrophages, resulting in discrete cell colonies. On the other hand, they can have an inhibitory effect on colony growth by synthesizing prostaglandin E (see Prostaglandins).
In the medulla and the inner zone of the cortical substance of the thymus lobules and thymus-dependent zones of all peripheral lymphs, organs (lymphs, nodes, spleen, lymph accumulations, tissues of the gastrointestinal tract), the so-called. interdigitating cells. They are characterized irregular shape nuclei and the presence of tubulovesicular structures in the cytoplasm. Their plasma membrane forms numerous protrusions that penetrate between similar formations of neighboring cells of the same type or lymphocytes. These cells are morphologically very similar to macrophages, as well as Langerhans cells localized in the epidermis (see Skin). Currently, most researchers are inclined to believe that interdigitating cells are specific stromal elements of thymus-dependent zones responsible for the migration and differentiation of T-lymphocytes.
Macrophages are involved in the synthesis of substances that modulate the proliferation and differentiation of lymphoid cells. These include a factor that activates lymphocytes and provides a mitogenic (blastogenic) response of T-lymphocytes to lectin and histocompatibility antigens (see Blastotransformation of lymphocytes), as well as factors that enhance the helper function of T-lymphocytes (increased antibody production in B-lymphocytes). Using cloning of B-lymphocytes, it was shown that macrophages produce a diffuse factor that promotes the formation of colonies by a subpopulation of B-lymphocytes. An excess number of macrophages, on the contrary, leads to suppression of the growth of colonies as a result of the production of prostaglandin E.
exchange function
Exchange process, in Krom the role of macrophages is reliably proved, the exchange of iron is. As a result of erythrophagocytosis in the macrophages of the bone marrow and spleen, iron accumulates in the form of specific needle-like or rod-shaped inclusions of ferritin and hemosiderin. Ferritin then enters by pinocytosis (see) in adjacent erythroblasts. With phenylhydrazine anemia, an increase in rod-shaped inclusions containing ferritin is observed in macrophages.
Bibliography: Mononuclear phagocytes, ed. by R. van Furth, Oxford-Edinburgh, 1970; Mononuclear phagocytes, In immunity, infection and pathology, ed. by R. van Furth, Oxford a. o., 1975; Mononuclear phagocytes, Functional aspects, ed. by R. van Furth, pt 1-2, Hague a. o., 1980.
H. G. Khrushchov, V. I. Starostin.
Defining the system of mononuclear phagocytes, it should be noted that it combines monoblasts, promonocytes, monocytes, and tissue macrophages of various structures, which were previously attributed to the reticuloendothelial system, bound together. Macrophages are long-lived phagocytic cells with most of the functions of neutrophils. They are important secretory cells that, through their receptors and secretion products, participate in a whole complex of immunological and inflammatory processes that are not mediated by neutrophils. Monocytes leave the bloodstream through the walls of blood vessels by diapedesis, and much more slowly than neutrophils, their half-life is 12-24 hours.
Once monocytes leave the bloodstream, they migrate to tissues where they differentiate into macrophages with specialized functions according to their anatomical location. Alveolar macrophages, stellate reticuloendotheliocytes of the liver (Kupffer cells), peritoneal macrophages, microgia cells of the brain, macrophages of the bone marrow, spleen, lymph nodes, dendritic macrophages have special functions. Factors secreted by macrophages include lysozyme, neutral proteases, acid hydrolases, arginase, a number of complement components, enzyme inhibitors (plasmin, a 2 -macroglobulin), binding proteins (transferrin, fibronectin, transcobalamin II), nucleosides, and interleukin-1 ( pyrogen). The latter performs many important functions, stimulates the hypothalamus, which is accompanied by a feverish reaction: it mobilizes leukocytes from the bone marrow, and also activates lymphocytes and neutrophils. Another group of products secreted by macrophages includes reactive oxygen metabolites, biologically active lipids (arachidonic acid metabolites and platelet activating factors), neutrophil chemoattractant, factors regulating protein synthesis of other cells, colony-stimulating factor relative to bone marrow cells, factors for stimulating fibroblasts and proliferation of microcirculation elements, as well as factors that inhibit the process of replication of lymphocytes, tumors, viruses and some types of bacteria (listeria). Macrophages also function as effector cells involved in the elimination of intracellular microorganisms. Their ability to fuse to form giant cells that form into granulomas in response to an inflammatory response is an important link in the elimination of intracellular microorganisms; this process may be under the control of y-interferon.
Macrophages play an important role in the immune response. They excite the antigen for presentation to lymphocytes, modulate the function of lymphoid cells, participate in the autoimmune reaction, removing immune complexes and other immunologically active substances from the bloodstream. In addition, macrophages play a role in wound healing, elimination of senescent, decaying cells, and the development of atheroma.
(Greek monox one + lat. nucleos nucleus: Greek phagos devouring, absorbing + histol. sutus cell; synonym: macrophage system, monocyte-macrophage system)
physiological defense system of cells that have the ability to absorb and digest foreign material. The cells that make up this system have a common origin, are characterized by morphological and functional similarities, and are present in all tissues of the body.
basis contemporary view about S. m. f. is the phagocytic theory developed by I.I. Mechnikov at the end of the 19th century, and the teaching of the German pathologist Aschoff (K. A. L. Aschoff) about the reticuloendothelial system (RES). Initially, RES was identified morphologically as a system of body cells capable of accumulating the vital dye carmine. On this basis, connective tissue histiocytes, blood monocytes, liver Kupffer cells, and reticular cells were classified as RES. hematopoietic organs, endothelial cells of capillaries, sinuses of the bone marrow and lymph nodes. With the accumulation of new knowledge and the improvement of morphological research methods, it became clear that ideas about the reticuloendothelial system are vague, not specific, and in a number of provisions are simply erroneous. For example, the reticular cells and endothelium of the sinuses of the bone marrow and lymph nodes have long been attributed the role of a source of phagocytic cells, which turned out to be incorrect. It has now been established that mononuclear phagocytes originate from circulating blood monocytes. Monocytes mature in the bone marrow, then enter the bloodstream, from where they migrate to tissues and serous cavities, becoming macrophages. Reticular cells perform a supporting function and create the so-called microenvironment for hematopoietic and lymphoid cells. Endothelial cells carry out the transport of substances through the walls of the capillaries. Reticular cells and vascular endothelium are not directly related to the protective system of cells. In 1969, at a conference in Leiden dedicated to the problem of RES, the concept of "reticuloendothelial system" was recognized as obsolete. Instead, the concept of "system of mononuclear phagocytes" is adopted. This system includes histiocytes of the connective tissue, Kupffer cells of the liver (stellate reticuloendotheliocytes), alveolar macrophages of the lungs, macrophages of the lymph nodes, spleen, bone marrow, pleural and peritoneal macrophages, osteoclasts bone tissue, microglia nervous tissue, synoviocytes synovial membranes, Langergais cells of the skin, pigmentless granular dendrocytes. There are free, i.e. moving through tissues, and fixed (resident) macrophages, having a relatively permanent place.
Macrophages of tissues and serous cavities, according to scanning electron microscopy, have a shape close to spherical, with an uneven folded surface formed by the plasma membrane (cytolemma). Under cultivation conditions, macrophages spread out on the surface of the substrate and acquire a flattened shape, and when moving, they form multiple polymorphic pseudopodia. A characteristic ultrastructural feature of a macrophage is the presence in its cytoplasm of numerous lysosomes and phagolysosomes, or digestive vacuoles (Fig. 1). Lysosomes contain various hydrolytic enzymes that ensure the digestion of the absorbed material. Macrophages are active secretory cells that release enzymes, inhibitors, and complement components into the environment. The main secretory product of macrophages is lysozyme. Activated macrophages secrete neutral proteinases (elastase, collagenase), plasminogen activators, complement factors such as C2, C3, C4, C5, and interferon.
Cells of S. m. f. have a number of functions, which are based on their ability to endocytosis, i.e. absorption and digestion of foreign particles and colloidal liquids. Thanks to this ability, they perform a protective function. Through chemotaxis, macrophages migrate to the foci of infection and inflammation, where they carry out phagocytosis of microorganisms, their killing and digestion. In conditions chronic inflammation may appear special forms phagocytes - epithelioid cells (for example, in an infectious granuloma) and giant multinuclear cells of the Pirogov-Langhans cell type and the foreign body cell type. which are formed by the fusion of individual phagocytes into a polykaryon - a multinuclear cell (Fig. 2). In granulomas, macrophages produce the glycoprotein fibronectin, which attracts fibroblasts and contributes to the development of sclerosis.
Cells of S. m. f. take part in immune processes. Thus, an indispensable condition for the development of a directed immune response is the primary interaction of a macrophage with an antigen. In this case, the antigen is absorbed and processed by the macrophage into an immunogenic form. Immune stimulation of lymphocytes occurs by direct contact with a macrophage carrying a converted antigen. The immune response as a whole is carried out as a complex multi-stage interaction of G- and B-lymphocytes with macrophages.
Macrophages have antitumor activity and exhibit cytotoxic properties against tumor cells. This activity is especially pronounced in the so-called immune macrophages, which lyse tumor target cells upon contact with sensitized T-lymphocytes carrying cytophilic antibodies (lymphokines).
Cells of S. m. f. take part in the regulation of myeloid and lymphoid hematopoiesis. Thus, hematopoietic islands in the red bone marrow, spleen, liver and yolk sac of the embryo form around a special cell - the central macrophage, which organizes erythropoiesis of the erythroblastic islet. Kupffer cells of the liver are involved in the regulation of hematopoiesis by producing erythropoietin. Monocytes and macrophages produce factors that stimulate the production of monocytes, neutrophils and eosinophils. IN thymus(thymus) and thymus-dependent zones of lymphoid organs, the so-called interdigitating cells were found - specific stromal elements, also related to S. m. f., responsible for the migration and differentiation of T lymphocytes.
The metabolic function of macrophages is their participation in iron metabolism. In the spleen and bone marrow, macrophages carry out erythrophagocytosis, while they accumulate iron in the form of hemosiderin and ferritin, which can be reutilized by erythroblasts.
Bibliography: Karr Jan. Macrophages: a review of ultrastructure and function, trans. from English, M., 1978; Persina I.S. Langerhans cells - structure, function, role in pathology, Arch. patol., t. 47, no. 2, p. 86, 1985.
Rice. Fig. 2. Electron diffraction pattern of a macrophage in the focus of aseptic inflammation: 1 - fragments of the bean-shaped nucleus; 2 - phagocytosed material in the digestive vacuole; ×21000.
Rice. Fig. 1. Electron diffraction pattern of a section of a giant multinucleated cell of foreign bodies: 1 - nuclei that are part of one cell; 2 - lysosomes; 3 - phagosomes; ×15000.
Watch value Mononuclear phagocyte system in other dictionaries
block system- block systems, w. (railroad). Blocking, blocking system. See (block).
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Explanatory Dictionary of Efremova
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